PROJECT SUMMARY/ABSTRACT Understanding the pathogenesis of neurological disorders caused by arboviruses is fundamental to the treatment of viral encephalitis using drug or vaccine therapy. Rift Valley Fever (RVF) is a globally-important emerging mosquito-transmitted disease that presents a significant risk to humans and livestock communities. The potential for global spread is high due to the pervasive mosquito vectors, and emergence would cause considerable economic damage (due to the agricultural impact) as well as fear and anxiety (due to human illness). The most understudied clinical disease caused by RVFV is encephalitis, which causes long-term morbidity in survivors as well as death in 50% of patients with neurological symptoms. This proposal is founded upon 3 scientific findings from our preliminary data: 1) There are appropriate encephalitic disease animal models after infection with a wild-type virulent strain of RVFV; 2) Overproduction of cytokines, chemokines, and matrix metalloproteinases (MMPs) correlates with neurological disease onset; and 3) Treatment with the antiviral therapeutic drug favipiravir is necessary but not sufficient to protect animals from lethal neurological disease. Taken together, the objective of this proposal is to understand the role of cytokine and MMP-mediated host inflammatory response in RVF-induced neurological disease, with the ultimate goal of designing therapeutic interventions to prevent neuropathology. We will address this objective using three complementary specific aims: In Aim 1, we will determine the kinetic mechanisms by which cytokines and MMPs modulate RVF CNS inflammation. Aim 2 will develop novel in vitro modeling systems to define RVFV-CNS cell interactions and screen therapeutic candidates. Aim 3 will test novel therapeutic regimens in a relevant animal model. This proposal will result in an understanding of the contribution of immunopathology to RVF neurological disease. Importantly, we will have identified a post-exposure treatment regimen to protect from neurological RVF. This proposal represents a critical step in the event of an epidemic of this emerging pathogen.